Diagnosis of breast cancer as well as the burden of breast cancer treatment put women at risk for psychosocial distress. Psychosocial distress impairs the immune system, impacting both natural killer cells and the production of cytokines. This is of particular importance to breast cancer patients because breast cancer can be responsive to natural killer cells and cytokines. These components of the immune system contribute to cancer control by protection from tumor initiation, primary tumor growth, and tumor metastasis. In the past decade, the number of women diagnosed with the form of breast cancer known as ductal carcinoma in situ (DCIS) has markedly increased. This increase in the number of DCIS patients is due to the widespread use of high- resolution screening mammography. DCIS is a significant clinical management problem and women diagnosed with DCIS face difficult treatment choices that must be weighed against not only the risk of cancer recurrence but also their personal values. Our preliminary data show that women with DCIS experience psychosocial distress that is characterized by elevated mood disturbance, anxiety, and perceived stress. Accompanying this psychosocial distress is immune dysregulation characterized by reduced natural killer cell function and reduced production of the cytokine interferon y. Such effects upon the immune system may have considerable impact upon the overall health and quality of life of breast cancer patients. However, surprisingly little is known about the molecular basis for the observed immune dysregulation. It is the overall purpose of this project to identify, at the molecular level, the basis for this immune dysregulation. This identification will be accomplished by determining whether peripheral blood mononuclear cell epigenetic modifications, subsequent to psychosocial-distress, mediate the immune-dysregulation. The specific aims of the project are to: 1) Identify peripheral blood mononuclear cell epigenetic patterns associated with psychosocial-distress mediated immune-dysregulation in women who are diagnosed with DCIS. 2) Evaluate whether epigenetic modifications are associated with specific dysregulated immune response genes in women with DCIS. This two-year developmental/pilot (R21) project will evaluate women with DCIS at 2 data collection time periods, one following breast cancer diagnosis and one 2 months after completion of cancer treatment. Results will be contrasted with a comparison group of matched women. The design of this project will provide for an identification of the peripheral blood mononuclear cell subsets, with demonstrable epigenetic pattern modification. Once identified, these subsets will be evaluated by chromatin immunoprecipitation and polymerase chain reaction to determine whether the observed epigenetic effects are associated with regulatory regions of specific immune response genes dysregulated in these women. No such analysis has been accomplished previously and this study will provide the first investigation of the epigenetic effects of psychosocial distress upon the immune system. Identification of an epigenetic basis for this immune-dysregulation will provide new insight into the effects of psychosocial-distress and will allow for future development of the means by which to manage this dysregulation. Such management will not only reduce the long-term adverse effects of immune-dysregulation but will also improve the overall health and quality of life of these patients.